IP Archives of Cytology and Histopathology Research

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Get Permission S. Subbiah, Susikar, Hussain, and Raja: The correlation of response to induction chemotherapy with neutrophil lymphocyte ratio and platelet lymphocyte ratio in oral cavity malignancy


Introduction

Squamous cell carcinoma of the head and neck (SCCHN) accounts for about 5% of all cancers in the West. In India, they form around 25-30% of all cancers and 60-70% of these present as locally advanced (stage III/IV) cancers.1,2 Induction chemotherapy using cisplatin based combination has yielded major response rates of upto 90% and clinical complete response rates of around 30% in locoregionally advanced head and neck SCC.3

Pre-treatment biomarkers can help to predict response to chemotherapy. The systemic inflammatory response has been regarded as an independent prognostic factor in patients with various malignancy.4 Neutrophils can facilitate tumour proliferation, invasion, and distant metastasis by secreting factors that promote tumour growth.5,6,7 Platelets are cells containing the largest quantity of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β and platelet-derived endothelial cell growth factor (PD-ECGF).8 These platelet-derived growth factors are often produced in large quantities by cancer cells and contribute to cancer growth and histology. In contrast, lymphocytes, particularly cytotoxic T cells, play a crucial role in the anti - tumour immune response by promoting apoptosis and suppressing tumour growth.9,10 Accordingly, the neutrophil–lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR) a re cost-effective and simple parameters that can predict response to chemotherapy.

This study aims to find the correlation between NLR, PLR and response to induction chemotherapy in oral cavity malignancies.

Materials and Methods

Details of 32 patients with locally advanced squamous cell carcinoma of oral cavity who received induction chemotherapy from Jan 2017- March 2019 were collected and the following were recorded.

  1. Pre - treatment total leukocyte count, neutrophil, lymphocyte, platelet counts. Using automated analyser

  2. Tumour size - Clinical, radiological, and post operative specimen.

Treatment and response assessment

Three cycles of chemotherapy are given:

Premedication (Inj Hydrocortisone 100 mg, InjOndansetron 8mg, Inj Pheniramine 10mg) were given half an hour before starting chemotherapy Day 1: Paclitaxel 175 mg/m2 as 3 hrs. infusion or Docetaxel 75 mg/m2 as 2 hours infusion, Cisplatin 75 mg/m2 as divided doses on Day 1 and Day 2 as 3 hrs infusion Day 2- Day 5: 5 Fluorouracil 750 mg/m2 as 24 hrs. continuous infusion Prophylactic GM-CSF given.

21 day cycle

The pretreatment clinical measurement of maximum tumour size and post operative histopathological maximum tumour size is compared for response assessment in operated patients. The radiological (CT or MRI) change in size post three cycles of induction chemotherapy is used in non - operated patients to assess response. Patients are grouped into three categories. Those with histopathological or radiological complete response are complete responders. Patients with more than 30% of reduction in tumour size are grouped as partial responders, and those with less than 30% of reduction in tumour size are grouped as non-responders.

Blood analysis for the determination of the NLR and PLR

The blood samples were collected before the initiation of chemotherapy. Complete blood counts were measured using peripheral blood samples with automated analyser. The total count, differential neutrophil, lymphocyte count and platelet counts were measured. AbsoluteNeutrophil and lymphocyte counts calculated. Neutrophil and lymphocyte ratio obtained. Platelet count divided by absolute lymphocyte count to obtain PLR ratio.

Statistical analysis

Software used is SPSS Statistics for windows, version 23.0, Armonk, NY :IBM Corp. Released 2015

The mean value of NLR was calculated for the three groups. Kruskal Wallis test was used to calculate the significance of variation between the three groups. The significance in variation of NLR between two groups was calculated using Mann- whitney U and Wilcoxon w test.

The mean PLR was calculated and the significance in change of PLR across the three groups analysed by ANOVA test. Inter group analysis of significance in change was done by post Hoc tests.

Results

Results for NLR

Table 1
N Mean Std. Deviation
Complete response group 7 2.494 .9688
Partial response group 18 2.622 1.5791
Static response group 7 5.614 2.1130
Total 32 3.249 2.0083

Mean NLR

The mean NLR is shown in Table 1. The mean NLR in the complete and partial response group is significantly low compared to static group.

Figure 1
https://s3-us-west-2.amazonaws.com/typeset-media-server/1ddeecb1-5f53-4e66-a887-7a64b1a229fcimage1.png

There is a statistically significant difference in NLR when the three groups are analysed together (p=.007). [Table 2]

Table 2
Group N Mean Rank
NLR Complete response group 7 14.21
Partial response group 18 13.56
Static response group 7 26.36
Total 32
NLR
Chi-Square 9.931
Df .007
Asymp. Sig. 2

Kruskal wallis test

Table 3

Intergroup comparison

(I) Group (j) Group P value
Complete response group Partial response group 0.785
Partial response group Static response group 0.003
Static response group Complete response group 0.009

Inter group analysis revealed that there is no statistical difference in NLR between complete and partial responders (p= 0.785). There is statistical difference in the mean NLR between the partial and static responders (p=0.003). Significant difference is observed between static and complete response group. (p=0.009). [Table 3].

Table 4
Group Total
Complete / Partial Response Group Static Response Group
NLR > = 3.95 Count 2 6 8
% within NLR 25.0% 75.0% 100.0%
< 3.95 Count 23 1 24
% within NLR 95.8% 4.2% 100.0%
Total Count 25 7 32
% within NLR 78.1% 21.9% 100.0%

ROC cutoff value for NLR

From ROC curve, a cutoff value of 3.95 is chosen.

When cutoff value of 3.95 is used 95.8% of patients with NLR below the value have either complete or partial response and 75% of patients with NLR above it are static responders [Table 4].

Results for PLR

The mean PLR in complete response group is 124. For partial response group the mean PLR is 137 and for the static response group is 180.[Table 5]

Figure 2
https://s3-us-west-2.amazonaws.com/typeset-media-server/1ddeecb1-5f53-4e66-a887-7a64b1a229fcimage2.png

Table 5
N Mean Std. Deviation
Complete response group 7 124.00 32.609
Partial response group 18 137.50 47.243
Static response group 7 180.43 44.328
Total 32 143.94 47.165

Mean PLR

Table 6
Anova Test
Sum of Squares df Mean Square F Sig.
Between Groups 12849.661 2 6424.830 3.320 .050
Within Groups 56112.214 29 1934.904
Total 68961.875 31

Significance of difference between groups (PLR)

There is no statistically significant difference in the mean when all the three groups are compared (p=0.05).[Table 5].

Table 7

Inter group analysis PLR

(I) Group (J) Group Mean Difference (I-J) Std. Error Sig.
Complete response group Partial Response Group -13.500 19.594 .772
Partial Response Group Static Response Group -42.929 19.594 .090
Static Response Group Complete Response Group 56.429 23.512 .058

As shown inTable 7, inter group analysis of mean PLR revealed that the re is no statistically significant difference in mean PLR between the complete and partial response groups (p=0.772). There is no significant difference in PLR between the partial and static response group (p=0.09) and static and complete response group (p=0.58).

Using ROC curves a cut-off value of 153 was determined, 94.7% of patients with PLR below 153 were responders to chemotherapy and 46.2% of patients with PLR above 153 were having static disease [Table 8]

Table 8
Group Total
Complete / Partial Response Group Static Response Group
PLR > = 153 Count 7 6 13
% within PLR 53.8% 46.2% 100.0%
< 153 Count 18 1 19
% within PLR 94.7% 5.3% 100.0%
Total Count 25 7 32
% within PLR 78.1% 21.9% 100.0%

ROC cutoff value PLR

Combined NLR and PLR

To identify the impact of combining NLR and PLR a score of 0 is assigned for patients who have low NLR and PLR., 1 for patients who have either low NLR or PLR and 2 for patients with high PLR and NLR.

Table 9
Score 0 1 2
Complete 6 1 0
Partial 11 6 1
Static 0 2 5

Combined NLR/PLR

As shown in table 9, no patient with high value of either NLR or PLR was present in the complete response group. None of the patients who had a low NLR or PLR was present in the static group. In the partial response group except for 1 patient the other 16 patients had either a low NLR or PLR.

Discussion

There are different original studies and meta-analysis that show a prognostic and predictive role for NLR in solid tumours, including head-and-neck malignancies. In the present study, pre - treatment NLR and PLR have been demon strated to be correlating with response to platinum-based chemotherapy in epithelial oral cavity malignancy.

The mean NLR is significantly low in bothpartial and complete response groups compared to the patients with static response. The mean PLR is also low in responders when compared to the static group but it is not statistically significant. With a cut-off value of 3.95 for NLR and 153 for PLR, response could be predicted with high positive predictive value. When both the ratios are combined the predictive value is further increased as shown in this study.

Only a few studies have been done to evaluate the significance of pre-treatment NLR or PLR in head and neck malignancies. In a study to evaluate the association between pre- treatment NLR and outcome for locally advanced oral cavity cancers, Perisanidis et al. obtained mean NLR of 2.6 for their patients who responded to chemotherapy.11 An et al. in a similar study reported mean NLR value of 3.07 for their total cohort of patients with nasopharyngeal cancer.9  Jin et al. compared outcome and response to platinum-based chemotherapy in metastatic nasopharyngeal carcinoma. They determined a cut -off of 3.6 for NLR, based on the median of the values and showed that the response (CR + PR) rate is better with low NLR values.12 Karpathiou et al. in a retrospective study, analysed the clinical and histologic predictive factors of response to induction chemotherapy in 81 HNC patients. The patients were divided into good (62%) and poor (38%) responder groups. They selected a cut-off of 7 for NLR, and no significant difference for response rate between the two groups of low and high NLR was detected although the survival was significantly different.13  The most common primary sites in their study were hypopharynx and oropharynx (totally 86%). The discrepancy between their results and our study may be explained with the different primary sites and also the unusual NLR cut -off selected by them.

Conclusion

Pretreatment NLR and PLR are reliable biomarkers of the systemic immunologic phenotype of the cancer patients. The se predict the response to chemotherapy in patients with oral cavity malignancy. Combining NLR and PLR has better predictive value than either of them taken alone.

Source of funding

None.

Conflict of interest

None.

References

1 

S A Pradhan Surgery for the cancer of the Buccal MucosaSemin Surg Oncol198955318321

2 

G K Rath P M Parikh S Hukku B Rajan S Kumar H Malhotra Indian Council of Medical Research consensus document for the management of buccal mucosa cancerIndian J Med Paediatr Oncol: official J Indian Soc Med & Paediatr Oncol2014352136

3 

D J Adelstein M Leblanc Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and neck cancerJ Clin Oncol2006241726242628

4 

H Nakashima Y Matsuoka R Yoshida M Nagata A Hirosue K Kawahara Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma: A retrospective studyBMC Cancer20161641

5 

S I Grivennikov F R Greten M Karin Immunity, inflammation, and cancer Cell2010140883899

6 

S Trellakis K Bruderek C A Dumitru H Gholaman X Gu A Bankfalvi Polymorphonuclear granulocytes in human head and neck cancer: Enhanced inflammatory activity, modulation by cancer cells and expansion in advanced diseaseInt J Cancer201112921832193

7 

S Chen J Guo C Feng Z Ke L Chen Y Pan The preoperative platelet-lymphocyte ratio versus neutrophil-lymphocyte ratio: Which is better as a prognostic factor in oral squamous cell carcinoma?Ther Adv Med Oncol20168160167

8 

P Balermpas Y Michel J Wagenblast O Seitz C Weiss F Rodel Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancerBr J Cancer2014110501509

9 

X An P R Ding F H Wang W Q Jiang Y H Li Elevated neutrophil to lymphocyte ratio predicts poor prognosis in nasopharyngeal carcinomaTumour Biol201132317324

10 

A Rassouli J Saliba R Castano M Hier A G Zeitouni Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinomaHead Neck201537103110

11 

M Hashemi-Bahremani N Mortazavi K Novin A Ameri Z Razzaghi Blood neutrophil-to-lymphocyte ratio as a predictor of response to chemotherapy in head-and-neck cancersJ Head Neck Physicians Surg201972025

12 

C Perisanidis G Kornek P W Pöschl D Holzinger K Pirklbauer C Schopper C High neutrophil-to-lymphocyte ratio is an independent marker of poor disease-specific survival in patients with oral cancerMed Oncol 30334

13 

Y Jin X Ye C He B Zhang Y Zhang Pretreatment neutrophil-to-lymphocyte ratio as predictor of survival for patients with metastatic nasopharyngeal carcinomaHead Neck2015376975



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Article type

Original Article


Article page

337-341


Authors Details

S. Subbiah, Sujay Susikar, Syed Afroze Hussain, Gerald Anand Raja


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